Protection of the Aged Myocardium

描述（由申请人提供）：随着美国人口的老龄化，预计到2035年，老年人（65岁以下）将从13-14%增加到25%。如果这一趋势继续下去，在未来50年里，50%的美国人口和全球20亿人口将“老龄化”。老年人的健康面临着巨大的挑战，因为衰老与无数的疾病有关。心血管疾病是美国发病率和死亡率的主要原因，50%的死亡率归因于冠状动脉疾病，其中80%的死亡发生在65岁及以上的人群中。老年心脏比年轻心脏对缺血性损伤更敏感。人们提出了几种理论来解释这种老龄化赤字。这些理论要么援引遗传的、生化的、分解代谢的或生理的成分。尽管与年龄相关的缺血耐受性缺陷的机制尚不清楚，但它们可能涉及细胞信号和线粒体的异常，这些异常是遗传、生化、分解代谢和生理缺陷的综合结果。针对这些机制的治疗方法有可能挽救老化的心肌。我们的初步研究表明，小窝蛋白定位于线粒体，可以调节线粒体的功能/动力学。我们提出以下假设：1)细胞将小窝蛋白转运到关键的调节节点（即肌层膜和线粒体）是对缺血应激的关键反应；2)在衰老心肌中，由于膜定位的小窝蛋白丢失，小窝蛋白向线粒体的细胞运输中断；3)老龄动物通过膜和线粒体靶向在不同的细胞区室中修复小窝蛋白可能是恢复心肌缺血耐受性的一种手段。具体目标1：确定膜定位的小窝蛋白的缺失是否会导致小窝蛋白表达/小窝形成的缺失，从而限制小窝蛋白向线粒体的运输，以及衰老心肌中膜靶向的小窝蛋白表达是否会恢复向线粒体的运输。具体目标2：确定衰老是否导致线粒体定位的小窝蛋白减少，从而改变线粒体功能（即活性氧的产生和mPTP的调节）和线粒体动力学（即，调节线粒体更新和线粒体自噬的融合裂变），以及线粒体靶向的小窝蛋白表达是否必要且足以恢复线粒体功能/动力学。特异性目的3：确定膜或线粒体中小窝蛋白的靶向表达对于恢复老年心脏缺血耐受性是否必要和充分。

DESCRIPTION (provided by applicant): With the aging of the United States population, it is estimated that the elderly (>65 years of age) will increase from 13-14% to 25% by 2035. If this trend continues, >50% of the United States population and >2 billion people worldwide will be "aged" in the next 50 years. Aged individuals face formidable challenges to their health, as aging is associated with a myriad of diseases. Cardiovascular disease is the leading cause of morbidity and mortality in the United States with >50% of mortality attributed to coronary artery disease and >80% of these deaths occurring in those age 65 and older. Aged hearts are more sensitive than young hearts to ischemic insults. Several theories have been proposed to account for this aging deficit. These theories either invoke a genetic, a biochemical, a catabolic, or a physiologic component. Though the mechanisms that underlie an age-related deficit in ischemic tolerance are not clear, they likely involve abnormalities in cellular signaling and mitochondria that are a combined result of genetic, biochemical, catabolic, and physiologic deficiencies. Therapeutics that target these mechanisms have potential to rescue the aged myocardium. Our preliminary studies show that caveolin is localized to motochondria and can modulate mitochondrial function/dynamics. We propose the following hypotheses: 1) targeted cellular trafficking of caveolin to key regulatory junctions (i.e., sarcolemmal membrane and mitochondria) is a critical response to ischemic stress; 2) cellular trafficking of caveolin to mitochondria is disrupted in the aged myocardium due to loss of membrane-localized caveolin; 3) restoration of caveolin in distinct cellular compartments via membrane and mitochondrial targeting in aged animals may provide a means to restore tolerance to myocardial ischemia. The following specific objectives will be addressed: Specific Aim 1: Determine if loss of membrane-localized caveolin leads to loss of caveolin expression/caveolae formation thus limiting trafficking of caveolin to mitochondria and if membrane-targeted expression of caveolin in aged myocardium restores trafficking to mitochondria. Specific Aim 2: Determine if aging results in reduced mitochondria-localized caveolin to alter mitochondrial function (i.e., reactive oxygen species generation and regulation of mPTP) and mitochondrial dynamics (i.e., fusion-fission to regulate mitochondrial turnover and mitophagy) and if mitochondria-targeted caveolin expression is necessary and sufficient to restore mitochondrial function/dynamics. Specific Aim 3: Determine if targeted expression of caveolin in membrane or mitochondria is necessary and sufficient to restore ischemic tolerance in aged hearts.